The Eph receptors represent the largest subgroup of the receptor tyrosine kinase (RTK) and they influence cell shape and migration by acting directly on the actin cytoskeleton. In addition, they can affect cell proliferation and survival. In view of their pivotal role in cell-migration and cell-cell interaction, it is not surprising that Eph receptors and ephrins play an important role in tumor growth and cancer cell metastasis. Elevated expression of certain Eph receptors and ephrins has indeed been associated with tumor angiogenesis in many types of cancers. Therefore, there is strong evidence that Eph receptor/ephrin signaling could provide a novel yet unexplored target for the development of effective anti-cancer treatments. Because many Eph receptors are also overexpressed in cancer cells, they could also be used as targets to deliver cytotoxic or anti-cancer agents selectively to the tumors. In fact, following binding of their ephrin ligands, the Eph receptors are actively internalized in the cell where are directed into lysosomes. Hence, our central hypothesis is that Eph receptor targeting ligands covalently linked to a variety of anti-cancer agents could represent novel and effective therapeutics that would selectively deliver cytotoxic agents to cancer cells via the Eph receptors. In particular, we will explore the ability of a selective peptide ligand to deliver toxic substances to cancer cells expressing the EphA2 receptor. Furthermore, we will explore a novel and alternative way to target the EphA4 receptor by direct targeting of its ligand binding domain. To achieve these goals we will combine modern medicinal chemistry with structure-based design, cancer cell biology and in vitro and in vivo pharmacology. Finally, the most promising compounds will be evaluated in cellular assays and ultimately in tumor xenograft studies with breast, lung and prostate cancer cell lines as well as endothelial cells. If proven successful, our studies may result in novel agents that would not only be more efficacious than the current chemotherapeutic compounds, but that would also enhance the quality of life during and after chemotherapy.